1. Field of the Invention
The present invention relates generally to providing biostable elastomeric coatings on the surfaces of implants which incorporate biologically active species having controlled release characteristics in the coating and relates particularly to providing a non-thrombogenic surface during and after timed release of the biologically active species. The invention is particularly described in terms of coatings on therapeutic expandable stent prostheses for implantation in body lumens, e.g., vascular implantation.
2. Related Art
In surgical or other related invasive procedures, the insertion and expansion of stent devices in blood vessels, urinary tracts or other locations difficult to otherwise access for the purpose of preventing restenosis, providing vessel or lumen wall support or reinforcement and for other therapeutic or restorative functions has become a common form of long-term treatment. Typically, such prostheses are applied to a location of interest utilizing a vascular catheter, or similar transluminal device, to carry the stent to the location of interest where it is thereafter released to expand or be expanded in situ. These devices are generally designed as permanent implants which may become incorporated in the vascular or other tissue which they contact at implantation.
One type of self-expanding stent has a flexible tubular body formed of several individual flexible thread elements each of which extends in a helix configuration with the centerline of the body serving as a common axis. The elements are wound in the same direction but are displaced axially relative to each other and meet, under crossing a like number of elements also so axially displaced, but having the opposite direction of winding. This configuration provides a resilient braided tubular structure which assumes stable dimensions upon relaxation. Axial tension produces elongation and corresponding diameter contraction that allows the stent to be mounted on a catheter device and conveyed through the vascular system as a narrow elongated device. Once tension is relaxed in situ, the device at least substantially reverts to its original shape. Prostheses of the class including a braided flexible tubular body are illustrated and described in U.S. Pat. Nos. 4,655,771 and 4,954,126 to Wallsten and U.S. Pat No. 5,061,275 to Wallsten et al.
Implanted stents have been used to carry medicinal agents, such as thrombolytic agents. U.S. Pat. 5,163,952 to Froix discloses a thermalmemoried expanding plastic stent device formulated to carry a medicinal agent in the material of the stent itself. Pinchuk, in U.S. Pat. No. 5,092,877, discloses a stent of a polymeric material which may have a coating associated with the delivery of drugs. Other patents which are directed to devices of the class utilizing bio-degradable or bio-sorbable polymers include Tang et al., U.S. Pat. No. 4,916,193, and MacGregor, U.S. Pat. No. 4,994,071.
A patent to Sahatjian, U.S. Pat. No. 5,304,121, discloses a coating applied to a stent consisting of a hydrogel polymer and a preselected drug such as a cell growth inhibitors or heparin. A further method of making a coated intravascular stent carrying a therapeutic material is described in Berg et al., U.S. Pat. No. 5,464,650, issued on Nov. 7, 1995 and corresponding to European Patent Application No. 0 623 354 A1 published Nov. 9, 1994. In that disclosure, a polymer coating material is dissolved in a solvent and the therapeutic material dispersed in the solvent; the solvent evaporated after application.
An article by Michael N. Helmus (a co-inventor of the present invention) entitled "Medical Device Design--A Systems Approach: Central Venous Catheters", 22nd International Society for the Advancement of Material and Process Engineering Technical Conference (1990) relates to polymer/drug/membrane systems for releasing heparin. Those polymer/drug/membrane systems require two distinct types of layers to function.
It has been recognized that contacting blood with the surface of a foreign body in vivo has a tendency to induce thrombogenic responses and that as the surface area of a foreign device in contact with host blood increases, the tendency for coagulation and clot forming at these surfaces also increases. This has led to the use of immobilized systemic anti-coagulant or thrombolytic agents such as heparin on blood contacting surfaces such as oxygen uptake devices to reduce this phenomenon. Such an approach is described by Winters, et al., in U.S. Pat. Nos. 5,182,317; 5,262,451 and 5,338,770 in which the amine functional groups of the active material are covalently bonded using polyethylene oxide (PEO) on a siloxane surface.
Another approach is described in U.S. Pat. No. 4,613,665 to Larm in which heparin is chemically covalently bound to plastic surface materials containing primary amino groups to impart a non-thrombogenic surface to the material. Other approaches for bonding heparin are described in Barbucci, et al., "Coating of commercially available materials with a new heparinizable material", Journal of Biomedical Materials Research, Vol. 25, pp. 1259-1274 (1991); Hubbell, J. A., "Pharmacologic Modification of Materials", Cardiovascular Pathology, Vol. 2, No. 3 (Suppl.), 121S-127S (1993); Gravlee, G. P., "Heparin-Coated Cardiopulmonary Bypass Circuits", Journal of Cardiothoracic and Vascular Anesthesia, Vol. 8, No. 2, pp. 213-222 (1994).
Moreover, drug elution rates for a coating containing a hydrophilic or a lipophobic drug is usually very fast initially when the coated device contacts body fluid or blood. One of the methods to reduce the so called "burst effect" is to add a membrane containing porosigen over the coating layer containing the biologically active material. See e.g., U.S. Pat. No. 5,605,696 to Eury et al. and U.S. Pat. No. to Helmus et al. U.S. Pat. No. 5,447,724. When the porosigen elutes, a porous membrane is formed and the drug in the undercoat will release. Even though the method might be quite successful to control the drug release, it increases the coating thickness, reduces the effective drug loading and introduces undesirable additional foreign materials into the patient. Hence, there is a need for a coating which reduces the burst effect but is not too thick and does not require the release of porosigens into the body.
With regard to stents, polymeric stents, although effective, may have mechanical properties that are inferior to those of metal stents of like thickness and weave. Metallic vascular stents braided of even relatively fine metal can provide a large amount of strength to resist inwardly directed circumferential pressure. A polymer material of comparable strength requires a much thicker-walled structure or heavier, denser filament weave, which in turn, reduces the cross-sectional area available for flow through the stent and/or reduces the relative amount of opens space in the weave. Also, it is usually more difficult to load and deliver polymeric stents using catheter delivery systems.
While certain types of stents such as braided metal stents may be preferred for some applications, the coating and coating modification process of the present invention is not so limited and can be used on a wide variety of prosthetic devices. Thus, in the case of stents, the present invention also applies, for example, to the class of stents that are not self-expanding, including those which can be expanded, for instance, with a balloon; as well as polymeric stents of all kinds. Other medical devices that can benefit from the present invention include blood exchanging devices, vascular access ports, central venus catheters, cardiovascular catheters, extracorpeal circuits, vascular grafts, pumps, heart valves, and cardiovascular sutures, to name a few. Regardless of detailed embodiments, applicability of the invention should not be considered limited with respect to implant design, implant location or materials of construction. Further, the present invention may be used with other types of implantable prostheses.
Accordingly, it is a primary object of the present invention to provide a coating and process for coating a stent to be used as a deployed stent prostheses, the coating being capable of effective controlled long-term delivery of biologically active materials.
Another object of the invention is to provide a coating and process for coating a stent prostheses using a biostable hydrophobic elastomer in which biologically active species are incorporated within a coating.
Still another object of the present invention is to provide a multi-layer coating and process for the delivery of biologically active species in which the percentage of active material can vary from layer to layer.
Yet another object of the present invention is to provide a multi-layer coating and process for the delivery of biologically active species from a coating with a non-thrombogenic surface.
Another object of the invention is to provide a coating for the delivery of biologically active species having a top layer or topcoat which reduces the initial release of the species, in which the topcoat is substantially free of pores or porosigens and covers less than the entire surface of the undercoat. The topcoat can cover less than the entire surface of the undercoat before and/or while the device is implanted.
A further object of the invention is to provide a multilayer coating for the delivery of biologically active species such as heparin having a fluorosilicone top layer.
A still further object of the invention is to provide a multi-layer coating for the delivery of biologically active species such as heparin having a surface containing immobilized polyethylene glycol (PEG).
Other objects and advantages of the present invention will become apparent to those skilled in the art upon familiarization with the specification and appended claims.